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N-HETEROARYL COMPOUNDS

This invention relates to certain N-heteroaryl compounds that are generally useful as medicaments, more specifically as medicaments for animals. The medicament can preferably be used for the treatment of helminth infections and the treatment of parasitosis, such as caused by helminth infections. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to animals in need of the treatments. This invention also relates to novel N-heteroaryl compounds and the preparation of said compounds. Moreover this invention relates to pharmaceutical compositions and kits comprising the compounds.

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Long range 13C-1H-coupling constants at bridgehead carbons in some naphthalene and quinoline derivatives, “cross” ring and “through” ring interactions

The 3JCH couplings at bridgehead carbons in naphthalene and quinoline derivatives have been classified as “through” ring and “cross” ring interactions.Further divisions of the couplings have been introduced in an attempt to rationalize the interactions such that they may be used for structural assignments.The influence of central ?-bond order and of the heterocyclic nitrogen atom on the couplings has been discussed.From a study of the 3J couplings at C-9 and C-10 in 45 quinoline derivatives the coupling constant ranges observed were “through” ring (via 9,10-bond): J94 4.9-6.1 Hz, J95 5.5-7.3 Hz, J10.8 4.1-5.3 Hz; “cross” ring: J92 11.0-13.5 Hz, J97 6.7-9.8 Hz, J10.3 4.4-7.3 Hz, J10.6 5.2-9.1 Hz.

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On the thermally induced rearrangement of 2-alkoxypyridines to N-alkylpyridones

Analogues of 2-methoxypyridine undergo rearrangement to N-methylpyridones under flash vacuum pyrolysis (FVP) conditions. Ethoxy derivatives undergo competitive ethyl migration and elimination of ethylene. Analogues of 4-methoxypyridine do not undergo rearrangement under FVP conditions, but demethylation on silica may occur. The ease of rearrangement follows the basicity of the alkoxyhetarene to some extent. The vapour-phase rearrangements have been contrasted to condensed-phase pyrolyses. and a four-centre transition state for the former is supported by computation. The rearrangement allows structural assignment to the two products from the reaction of 2,4-dichloroquinoline with pyrrolidine.

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Design, synthesis and biological evaluation of 4-anilinoquinoline derivatives as novel potent tubulin depolymerization agents

A series of novel 4-anilinoquinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, 14h exhibited the most potent cytotoxic activity with IC50 values ranging from 1.5 to 3.9 nM against all tested cancer cell lines, and showed promising efficacy in multidrug resistant cancer cells. Flow cytometry assay, immune-fluorescence staining, microtubule dynamics assays and competition assays with EBI identified that 14h was a novel tubulin depolymerization agent by binding to the colchicine site. Importantly, in vivo efficacy evaluation of HCT116 xenograft model, 14h showed efficient antitumor activity without significant loss in body weight. All the results indicated that 14h could be a promising candidate for the treatment of cancer.

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Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent Gram-positive antibacterial activity

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.

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Palladium-catalyzed c-4 selective coupling of 2,4-dichloropyridines and synthesis of pyridine-based dyes for live-cell imaging

An alternative process of Pd-catalyzed C-4 selective coupling of 2,4-dichloropyridines with boronic esters was developed, which afforded 24 examples of C-4 coupled pyridines in moderate to good yields. After further arylation, 21 examples of C-2, C-4 diarylated pyridines with a significant photophysical property were obtained, which were applied as pyridine-based dyes into live-cell imaging with good biocompatibility and low toxicity.

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Arylidenes of Quinolin-2-one scaffold as Erlotinib analogues with activities against leukemia through inhibition of EGFR TK/ STAT-3 pathways

A new series of 6-substiuted-4-(2-(4-substituted-benzylidene)hydrazinyl)quinolin-2(1H)-one derivatives have been designed and synthesized. The structure of the synthesized compounds was proved by 1H NMR, 13C NMR, 2D NMR, mass and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, the most active compounds were further examined against the most sensitive leukemia RPMI-8226 and on healthy cell lines. 6-Chloro-derivative was the most active one; with IC50 = 15.72 ¡À 1.21 and 46.05 ¡À 2.36 muM against RPMI-8226 and normal cell lines, respectively. Also, it showed a remarkable inhibitory activity compared to gefitinib on the EGFR TK mutant, wild and on H-RAS in addition to STAT-3 with IC50 = 695.49 ¡À 21.8, 263.15 ¡À 15.13, 10.61 ¡À 0.27 and 1.753 ¡À 0.81 nM, respectively. Cell cycle analysis of RPMI-8226 cells treated with the 6-chloro-derivative showed cell cycle arrest at G2/M phase (supported by Caspases-3,8, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking studies ROCS analysis and Tanimoto scores supported the results. The study illustrated the effect of several factors on compounds activity.

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In homogeneous catalysis, the catalyst is in the same phase as the reactant. The number of collisions between reactants and catalyst is at a maximum.In a patent, 1055361-35-7, name is 4-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile, introducing its new discovery. Formula: C19H11F3N2O4S

Syntheses of acetylquinolines and acetylisoquinolines via palladium-catalyzed coupling reactions

Acetylquinolines and acetylisoquinolines were obtained from the corresponding chloro-, bromo- or trifluoromethylsulfonyloxy-heteroaromatics via four different palladium-catalyzed coupling reactions: (i) Stille coupling with tri(n-butyl)-1-ethoxyvinylstannane; (ii) Negishi coupling with 1-ethoxyvinylzinc chloride; (iii) cross-coupling with tri(1-ethoxyvinyl)indium; (iv) Heck arylation of n-butyl vinyl ether.

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Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis -stilbene diamines: A platform for the preparation of single-enantiomer cis -imidazolines for protein-protein inhibition

The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.

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Design and synthesis of quinolinones as methionyl-tRNA synthetase inhibitors

Five new structural analogues of substituted-1H-quinolinones (19, 20, 23, 24, and 26) have been synthesized and evaluated for Staphylococcus aureus methionyl-tRNA synthetase enzyme inhibitory activity. These compounds were also tested against pathogens of six S. aureus, two Enterococcus faecalis, and one Enterococcus faecium. Among all the synthesized quinolinones, compound 20 displayed significant inhibitory activities in the strains of E. faecalis and E. faecium.

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